Innate immune responses are dictated by a panel of pathogen recognition receptors, downstream signaling from the receptors and the stimulated activities of various effector molecules. IRF8 is known as an interferon (IFN)-responsive transcription factor that plays critical roles in regulating the development of myeloid and dendritic cells and the activity of a number of genes, such as IL-12 and iNOS, involved in innate responses. Much of the activity of IRF8 in vitro was previously shown to require its ability to heterodimerize with PU.1 and other transcription factors to mediate transcriptional activation or repression. An in vivo test of this model was provided by studies of BXH2 mice that identified a point mutation in IRF8 in the domain required for heterodimerization. It was shown that mice bearing this mutation were very similar to those bearing a null mutation of the gene, but that the null and point-mutant mice differed in their patterns of dendritic cell maturation. This indicated that most, but not all in vivo activities of IRF8 are dependent on its ability to dimerize with other transcription factors. Previous studies demonstrated that IRF8 is expressed to varying extents in cells of bone marrow origin. Recent evidence indicates broader than expected expression patterns of IRF8 in other non-hematopoietic tissues. To permit examinations of IRF8 expression on a single cell basis, we generated an IRF8 reporter mouse that expresses an IRF8-EGFP fusion protein under the control of normal endogenous IRF8 regulatory sequences. Expression levels were found to vary widely during various stages of hematopoietic differentiation with hematopoietic stem cells expressing little if any while dendritic cells expressed very high levels. Importantly, examining levels of IRF8-EGFP expression made it possible to define three subsets of what was previously thought to be a homogeneous population of granulocyte-myeloid progenitors. Interestingly, we found that IRF8 is expressed in gastric mucosa. These findings provide new insights into the expression and functions of IRF8 in a variety of tissues. In collaborations with Charles Egwuagu of NEI, we also examined the roles played by IRF8 in the development of autoimmune uveitis, an inflammatory disease. The disease was more severe if T cells were rendered deficient in IRF8 whereas protection was conferred by deletion of IRF8 in the retina. Finally we showed in this collaboration that the ocular pathology associate with eye infections by HSV-1 was limited by IRF8 by restraining the activation of CD8 T cells. We also engineered the development of two mouse strains that express mutant human TREX1 proteins associated with the development of two human diseases, systemic lupus erythematosus and cerebral retinal vasculopathy. Studies of the latter strain demonstrated that cell from these mice demonstrated a number of the biochemical abnormalities expressed by cells from humans with cerebral retinal vasculopathy indicating that it amy prove to be a model for testing therapeutic interventions as well understanding disease pathogenesis.